1-phosphanorbornene-dimethyl xanthene chiral ligand as well as synthesis method and application of 1-phosphanorbornene-dimethyl xanthene chiral ligand

Abstract

The invention provides a 1-phosphorus-doped norbornene-dimethyl xanthene chiral ligand as well as a synthesis method and application of the 1-phosphorus-doped norbornene-dimethyl xanthene chiral ligand. The structural formula of the chiral ligand is shown as a formula III and a formula III ': # imgabs0 #, a group R is C1-6 alkyl, C1-6 alkoxy, C1-6 alkenyl, phenyl, halogenated phenyl, C1-6 alkyl substituted phenyl or C1-6 alkoxy substituted phenyl, and a group R1 is C1-6 alkyl. The chiral ligand serves as a chiral phosphine ligand with a novel structure, three completely bound P-C bonds are formed through introduction of a rigid framework, the scientific problem that a phosphorus chiral center is easy to racemize is successfully solved, the phosphorus chiral ligand can be widely applied to asymmetric reactions such as asymmetric cyclization catalyzed by metal, and the phosphorus chiral ligand has a wide application prospect. And the method has a wide commercial application prospect. The synthesis method of the chiral ligand comprises the steps that the 9, 9-dimethyl xanthene compound and the 1-phosphorus-doped norbornene amine compound serve as raw materials, the chiral ligand is generated through H [1, 5] migration and phosphorus-doped D-A reaction, and the synthesis method is simple, good in feasibility and high in yield.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a 1-phosphanorbornene-dimethylxanthene chiral ligand and a synthesis method and application thereof. Background Art

[0002] Spirobarbiturates are barbituric acid derivatives. These compounds are difunctionalized at the C-5 position of barbituric acid to obtain a unique spirocyclic structure. Studies have shown that spirobarbituric acid compounds have important application prospects in the biomedical field, especially spirocyclic compounds composed of barbituric acid and a six-membered ring. Spirobarbituric acid-cyclohexane compounds have significant anti-tumor activity (J. Med. Chem., 1964, 7, 695); spirobarbituric acid-azacycloalanine compounds are used as anticonvulsant drugs (Pharm. Chem. J., 2009, 43, 315); spirobarbituric acid-pyrimidone compounds have strong urease inhibitory activity (Iran. J. Pharm. Res., 2015, 14, 1105); spirobarbituric acid-cyclohexanone compounds show HIV-1 inhibitor activity (Org. Biomol. Chem., 2011, 9, 7282). Therefore, the development of a new functional group synthesis method for spirobarbituric acid will further enrich the structural diversity of spirobarbituric acid compounds and promote further development in this field. Metal catalysts are commonly used in the synthesis process of barbituric acid compounds, and metal catalysts can affect the structure of the compounds. Therefore, the development of new metal catalysts is conducive to further enriching spirobarbituric acid compounds.

[0003] In the field of catalysis, chiral ligands can control the reactivity and selectivity of metal catalysts. Among the many types of chiral ligands, chiral phosphorus ligands are favored by organic chemists due to their excellent reactivity and chiral induction ability. In the development of chiral phosphine ligands, chemists often focus on the selection of chiral skeletons, and pay less attention to the synthesis of chiral phosphorus ligands with phosphorus chiral centers. The properties of phosphorus itself also lead to cumbersome synthesis steps of phosphorus chiral centers and the easy racemization of phosphorus chiral centers at high temperatures, so there are very few studies on phosphorus chiral center ligands. However, the activity and enantioselectivity of reactions in metal catalysis often depend on the electrical properties, acidity and alkalinity of chiral ligands, so slight changes in chiral ligands can often affect the rate-determining step of the catalytic reaction. Phosphorus chiral center ligands can change the electronic effect and steric hindrance of the ligand by changing the substituents on the phosphorus atom. In addition, the chiral site of this type of ligand is closer to the reaction substrate, which increases the possibility of chiral induction and transfer. These advantages of phosphorus chiral center ligands have prompted chemists to work hard to design and synthesize new phosphorus chiral ligands, aiming to overcome the shortcomings of cumbersome synthesis steps and easy racemization that restrict their development, and design and synthesize new phosphorus chiral ligands. Because the properties of phosphorus itself make phosphorus chiral centers difficult to synthesize and easy to racemize at high temperatures, there are very few studies on phosphorus chiral center ligands.

[0004] In the prior art, there are still few chiral phosphorus ligands designed with phosphorus chiral centers by embedding phosphorus atoms into rigid skeletons. The design and development of new chiral phosphorus ligands with phosphorus chiral centers are of great significance for the synthesis of spirobarbituric acid compounds. Summary of the invention

[0005] In view of this, one of the purposes of the present invention is to provide a 1-phosphanorbornene-dimethylxanthene chiral ligand, the structural formula of the chiral ligand is shown in the following formula III or III':

[0006]

[0007] In the above structural formula, the group R is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkenyl, phenyl, halogenated phenyl, C 1-6 Alkyl substituted phenyl or C 1-6 Alkoxy substituted phenyl group, group R 1 C 1-6 alkyl.

[0008] Among them, in the present invention, the "C 1-6 Alkyl", "C 1-6 Alkoxy", "C 1-6 "Alkenyl" refers to alkyl, alkoxy, and alkenyl groups containing 1 to 6 carbon atoms.1-6 The "alkyl" includes aliphatic alkyl and cycloalkyl. The number of substituents in the various "substituted phenyl" groups can be one, two or three, preferably one substituent.

[0009] Preferably, the group R is methyl, ethyl, propyl, butyl, allyl, phenyl, benzyl, 4-tert-butylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyclohexylphenyl, 2-methylphenyl, 3-methylphenyl, 3-chlorophenyl or 3,5-dimethylphenyl, and the group R 1 It is hydrogen or tert-butyl.

[0010] The second object of the present invention is to provide a method for synthesizing the above-mentioned chiral ligand, comprising using 9,9-dimethyloxanthene compounds and 1-phosphanorbornene amine compounds as raw materials, and generating the above-mentioned 1-phosphanorbornene-dimethyloxanthene chiral phosphine ligand through H[1,5] migration and phospha-DA reaction, wherein the structural formula of the 9,9-dimethyloxanthene compounds is shown in the following formula I, and the structural formula of the 1-phosphanorbornene amine compounds is shown in the following formula II or II'; the reaction formula is shown as follows:

[0011]

[0012]

[0013] In order to improve the reaction efficiency, the molar ratio of the compound I to the compound II is preferably 1:1-1.5.

[0014] The first organic solvent is mainly used to dissolve the reaction raw materials, and can be anhydrous methanol, ethanol, dichloromethane, tetrahydrofuran, etc.

[0015] The main function of the desiccant is to dry the byproduct water generated during the reaction, and the desiccant may be anhydrous magnesium sulfate, anhydrous sodium sulfate, etc. The amount of the desiccant used is preferably 5 to 10 equivalents.

[0016] The reducing agent is mainly used to reduce the generated imine intermediate, and can be sodium borohydride, sodium cyanoborohydride, etc. The amount of the reducing agent is preferably 1 to 1.2 equivalents.

[0017] The above-mentioned synthesis method specifically includes: taking the 9,9-dimethyloxanthene compound and the 1-phosphanorbornene amine compound in a first Schlenk bottle of a certain volume, adding the first organic solvent and the desiccant, and heating and refluxing at 60-80°C until the reaction is complete; placing the reaction system in an ice water bath, adding the reducing agent, and then continuing the reaction in the ice water bath until the reaction is complete, quenching the reaction, and synthesizing the above-mentioned 1-phosphanorbornene-dimethyloxanthene chiral ligand. Preferably, the heating reflux time is 1-3h to ensure that compounds I and II react completely. The reaction time in the ice water bath is preferably 2-4h.

[0018] Further, after the chiral ligand is synthesized, it is extracted with ethyl acetate, the organic layers are combined, and MgSO 4 Dry, filter, evaporate the solvent under reduced pressure, and separate by column chromatography to obtain the corresponding product with a yield of 50-78%.

[0019] The synthesis method of the compound I comprises the following steps:

[0020] Synthesis of compound I-2: First, compound I-1 and n-butyl lithium are used as raw materials to undergo lithiation reaction in an ice-water bath, and then iodine is added to react at room temperature to synthesize compound I-2. The reaction formula is as follows:

[0021]

[0022] Synthesis of compound I: First, the compound I-2 and n-butyl lithium are reacted at low temperature as raw materials, diphenylphosphine chloride is added to react, and then n-butyl lithium is added to react under alkaline conditions to synthesize the compound I. The reaction formula is as follows:

[0023]

[0024] The steps of synthesizing compound I-2 specifically include: firstly adding compound I-1 into a second Schlenk flask, replacing N 2 Afterwards, dissolve it with anhydrous ether, place it in an ice-water bath, add alkaline substances, slowly add n-butyl lithium, remove the ice-water bath, and place the Schlenk bottle at 30-50°C for reaction for 3-5h; cool it to 0°C, slowly add iodine dissolved in tetrahydrofuran, warm it to room temperature, and react overnight. After TLC detects that the reaction is complete, treat the unreacted iodine with a saturated sodium thiosulfate solution, extract with ethyl acetate, combine the organic phases, dry with anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography to obtain the compound I-2.

[0025] The steps of synthesizing compound I specifically include: placing the compound I-2 in a third Schlenk bottle, dissolving it with anhydrous tetrahydrofuran after replacing nitrogen, and cooling it at -78°C, then slowly dropping n-butyl lithium therein, reacting at -78°C for 1 to 2 hours, slowly dropping diphenylphosphine chloride, continuing the reaction for 0.5 to 1.5 hours, then adding n-butyl lithium therein, reacting for 1 to 2 hours, adding alkaline substances, reacting at -78°C for 1.5 to 2.5 hours, then slowly warming to room temperature, reacting overnight, after the reaction is completed by TLC detection, adding water to quench the reaction, extracting with ethyl acetate, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to obtain the compound I.

[0026] The synthesis method of the 1-phosphanorbornene amine compound comprises the following steps:

[0027] Synthesis of compound II-4: Compound II-3, tert-butylsulfenamide and tetraisopropyl titanate are used as raw materials to undergo a condensation reaction to generate compound II-4. The reaction formula is as follows:

[0028]

[0029] Synthesis of compounds II-5 and II-5': Compound II-4 and Grignard reagent RMgBr were used as raw materials, and compounds II-5 and II-5' were synthesized in an ice-water bath. The reaction formula is as follows:

[0030]

[0031] Synthesis of compound II: The compound II-5 or II-5' is first subjected to a reduction reaction under nickel catalysis, and then reacted with dilute hydrochloric acid to remove the sulfinyl group, thereby synthesizing the 1-phosphanorborneneamine compound II or II'. The reaction formula is as follows:

[0032]

[0033] The steps of synthesizing compound II-4 specifically include: placing compound II-3, tert-butylsulfenamide and tetraisopropyl titanate in a fourth Schlenk flask of a certain volume, replacing N 2 Afterwards, it was dissolved in dry tetrahydrofuran, the reaction temperature was 60-80°C, and after 2-4 hours of reaction, the reaction was monitored by TCL. After the reaction was detected to be complete, ethyl acetate was added thereto for extraction, and the organic phase was dried and filtered over anhydrous magnesium sulfate, rotary evaporated, and then subjected to column silica gel chromatography to obtain the diastereoisomer compound II-4.

[0034] The steps of synthesizing compounds II-5 and II-5' include: placing the compound II-4 in a fifth Schlenk bottle, replacing N2 Then dissolve it with tetrahydrofuran, place it in an ice-water bath, slowly add the Grignard reagent RMgBr at 0°C, react at 0°C for 0.5-1.5h, and after TLC detection, quench the reaction with water and extract with ethyl acetate; combine the organic phases, dry them with anhydrous magnesium sulfate, filter them and spin dry them; separate them on a silica gel column to obtain compounds II-5 and II-5'.

[0035] The step of synthesizing the 1-phosphanorbornene amine compound comprises: placing Raney nickel in a sixth Schlenk bottle after nitrogen has been evacuated, washing the Raney nickel with ethanol, then adding the compound II-5 or II-5', filtering out the Raney nickel, and rotating the remaining reaction liquid to dryness, dissolving the obtained solid with methanol, adding dilute hydrochloric acid, reacting at room temperature for 1 to 3 hours, and detecting the reaction by TLC. After the reaction is complete, extracting with saturated sodium bicarbonate and ethyl acetate, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, rotating to dryness, and filtering with a silica gel column to obtain the 1-phosphanorbornene amine compound II or II'.

[0036] The third object of the present invention is to provide an application of the above-mentioned chiral ligand in the preparation of spirobarbituric acid-epoxyhexane compounds. Preferably, the diastereoselectivity of the spirobarbituric acid-epoxyhexane compounds is greater than 20:1 and / or the stereoselectivity is greater than 98%. Specifically, alkenyl barbituric acid is used as an electron-deficient olefin, and phenyl-substituted 2-hydroxyallyl carbonate tert-butyl ester is synthesized by an asymmetric (4+2) cycloaddition reaction under palladium catalysis. This overcomes the defect that effective stereoinduction cannot be achieved when using traditional chiral ligands.

[0037] Preferably, the structural formula of the spirobarbituric acid-epoxyhexane compound can be Among them, R 2 C 1-6 Alkyl, C 1-6 Alkoxy, hydrogen, halogen, halo 1-6 Alkyl, nitro or naphthyl, R 3 C 1-6 Alkyl, C 1-6 Alkoxy, hydrogen, halo or naphthyl; R 4 C 1-6 Alkyl, or benzyl.

[0038]

[0039] Specifically, the preparation method of the above-mentioned spirobarbituric acid-epoxyhexane compound includes: mixing a palladium catalyst, the above-mentioned chiral ligand, a base and a second organic solvent under a nitrogen atmosphere to obtain a mixed system, and then adding the compound XX1 and the compound XX2 to the mixed system, reacting at 0 to 25° C. for 20 to 28 hours, and concentrating and purifying after the reaction is completed to obtain a spirobarbituric acid-epoxyhexane compound P.

[0040] The molar ratio of the compound XX1 to the compound XX2 is preferably 1 to 2:1 to improve the reaction efficiency.

[0041] Preferably, the palladium catalyst is Pd 2 (dba) 3 ·CHCl 3 , Pd 2 (dba) 3 、Pd(dba) 2 or Pd(PPh 3 ) 4 The molar ratio of the compound XX2 is preferably 0.05 to 0.2:1.

[0042] The main function of the chiral ligand is to regulate the stereoconfiguration of the product, and the molar ratio of the chiral ligand to compound XX2 is preferably 0.05 to 0.3:1.

[0043] The main function of the base is to promote hydrogen transfer during the reaction, and can be an inorganic base or an organic base, wherein the inorganic base can be cesium carbonate, sodium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium phosphate or potassium carbonate, etc., and the organic base can be 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), DBU, 1,4-diaminobicyclo[2.2.2]octane (DABCO) or triethylamine, etc. The molar ratio of the base to compound II is preferably 0.3 to 4:1 to improve the reaction yield.

[0044] The second organic solvent is mainly used to dissolve the reaction raw materials, and can be ethyl acetate, tetrahydrofuran, dichloromethane, chloroform, toluene, acetonitrile, etc.

[0045] Therefore, compared with the prior art, the present invention has the following beneficial effects:

[0046] 1) The 1-phosphanorbornene-dimethylxanthene chiral ligand provided by the present invention is a type of chiral phosphine ligand with a novel structure. By introducing a rigid skeleton, three completely bound PC bonds are formed, which successfully solves the scientific problem that the phosphorus chiral center is easy to racemize. Such phosphorus chiral ligands can be widely used in asymmetric reactions such as metal-catalyzed asymmetric cyclization, and have broad commercial application prospects;

[0047] 2) The synthesis method of the 1-phosphanorbornene-dimethylxanthene chiral ligand provided by the present invention is simple, feasible and has a high yield;

[0048] 3) The 1-phosphanorbornene-dimethylxanthene chiral ligand provided by the present invention can be used to prepare spirobarbituric acid-epoxyhexane compounds, which have the characteristics of good stereoselectivity, mild reaction conditions, simple and safe operation, cheap and easy to obtain raw materials, high reaction yield, etc., and the reaction yield can reach 50-96%;

[0049] 4) It has been verified that the spirobarbituric acid-epoxyhexane compounds provided by the present invention have anti-tumor activity and are expected to be used as anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of 1-phosphanorbornene-dimethylxanthene chiral ligand III-8;

[0051] Figure 2 is the H NMR spectrum of spirobarbituric acid-epoxyhexane compound P10;

[0052] Figure 3 This is a graph showing the results of an in vitro antitumor activity test of the spirobarbituric acid-epoxyhexane compound P10. DETAILED DESCRIPTION

[0053] The technical solution of the present invention is further described in detail below through specific implementation methods.

[0054] Unless otherwise specified, the terms used in the present invention are all commonly used terms in the relevant field. The technical means used in the examples, such as preparation processes, testing methods, etc., are all conventional means well known to those skilled in the art; the raw materials used in the examples are all commercially available.

[0055] 1. 1-phosphanorbornene-dimethylxanthene chiral ligand and preparation method thereof

[0056] The synthesis method of compound I in Example 1 is as follows:

[0057]

[0058] Take a 250 mL Schlenk bottle, add 2.1 g (10 mmol) of 9,9' dimethylxanthene, and replace N 2After that, it was dissolved with anhydrous ether, placed in an ice-water bath, 2.2 eq. of TMEDA was added, and then 3.0 eq. of n-butyl lithium was slowly added dropwise. The ice-water bath was removed, and the reaction bottle was placed at 40°C. After reacting for 4 hours, the temperature was lowered to 0°C, and iodine dissolved in tetrahydrofuran was slowly added. After warming to room temperature, the reaction was allowed to proceed overnight. After TLC detected that the reaction was complete, the unreacted iodine was treated with a saturated sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 2 was separated by column chromatography as a white solid.

[0059]

[0060] Take a 50mL Schlenk bottle, add the separated 2 therein, replace the nitrogen, dissolve it with anhydrous tetrahydrofuran, and place it at -78°C. After cooling for 10 minutes, slowly add 1.0eq. of n-butyl lithium dropwise, react at -78°C for 1.5h, slowly add 1.0eq. of diphenylphosphine chloride dropwise, continue to react for 1h, add 2.0eq. of n-butyl lithium therein, react for 1.5h, add 2.0eq. of DMF, react at -78°C for 2.0h, slowly warm to room temperature, react overnight, after TLC detection, add water to quench the reaction, extract with ethyl acetate, combine the organic phases, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and pass through a column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain I as a white solid.

[0061] The synthesis method of compound II in Example 2 is as follows:

[0062]

[0063] Take a 50 mL Schlenk bottle, put compound 3, 1.2 equivalents of tert-butylsulfenamide, and 2 equivalents of tetraisopropyl titanate in it, and replace N 2 After that, it was dissolved in dry tetrahydrofuran. The reaction temperature was 70°C. After 3 hours of reaction, the reaction was monitored by TLC. After the reaction was detected to be complete, ethyl acetate was added thereto for extraction. The organic phase was dried and filtered over anhydrous magnesium sulfate and evaporated to dryness. Then, it was subjected to column silica gel chromatography to obtain a pair of diastereomers 4.

[0064]

[0065] The diastereomer 4 obtained in the previous step was placed in a 25 mL Schlenk bottle and N 2Then, the mixture was dissolved in tetrahydrofuran, placed in an ice-water bath, and 2 equivalents of Grignard reagent were slowly added dropwise at 0°C. The mixture was reacted at 0°C for 1 hour. After TLC detection, the reaction was complete, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. Compounds 5 and 5' were separated by silica gel column.

[0066]

[0067] Take a 25mL Schlenk bottle, replace nitrogen, add an appropriate amount of Raney nickel, wash the Raney nickel three times with ethanol, and then wash it three times with tetrahydrofuran, then add compound II-5 or II-5' dissolved in tetrahydrofuran, and detect the reaction by TLC. After the reaction is complete, filter out the Raney nickel, and spin dry the remaining reaction liquid. After dissolving the obtained solid with methanol, add 2 equivalents of dilute hydrochloric acid, react at room temperature for 2 hours, and detect the reaction by TLC. After the reaction is complete, extract with saturated sodium bicarbonate and ethyl acetate, combine the organic phases, dry with anhydrous magnesium sulfate, filter, spin dry, and filter with a silica gel column to obtain compound II or II'.

[0068] Example 3 The synthesis method of compounds III-1 to III'-16, the steps are as follows:

[0069]

[0070] Compound I and compound II or II' were respectively placed in a Schlenk bottle, anhydrous methanol was added, and then anhydrous magnesium sulfate was added, and the mixture was heated to reflux at 70°C for 2 hours. The reaction progress was monitored by TLC. When the reaction was complete, the reaction system was placed in an ice-water bath, and 1.1 equivalents of sodium borohydride were slowly added. The reaction was continued at this temperature for 3 hours until the reaction was complete, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layers were combined and MgSO 4 Dry, filter, evaporate the solvent under reduced pressure, and separate by column chromatography; obtain the corresponding products III-1 to III-16 or their corresponding isomers with a yield of 50-78%.

[0071]

[0072] White solid.Yield:70%.MP:125-126.5℃.[α] D =-111(c=0.1,CH 2 Cl 2, 29.4℃). 31 P NMR

[0073] (121MHz,CDCl 3 )δ-16.98(s),-20.27(s)ppm. 1H NMR(300MHz,CDCl 3 )δ7.50-7.29(m,13H),7.26-7.13(m,8H),7.09-6.92(m,8H),6.56-6.52(m,1H),3.98(dd,J=10.0,5.5Hz,1H),3.33-3.19(m,2H),2.93(d,J=6.9Hz,1H),2.82(t,J=6.0Hz,1H),2.41(s,1H),1.67(s,3H),1.63(s,3H),1.54(s,3H),1.47-1.41(m,1H),1.39(s,9H),1.18(s,3H),0.84(t,J=10.6Hz,1H)ppm. 13 C NMR(75MHz,CDCl 3 )δ152.91(s),151.54(d,J=15.6Hz),149.85(s),148.19(s),142.29(s),142.20(s),142.07(s),139.25(s),139.06(d,J=2.8Hz),138.97(s),136.39(d,J=10.6Hz),135.81(d,J=10.1Hz),134.43(s),134.17(s),133.93(s),133.66(s),131.26(s),129.66(d,J=1.2Hz),129.32(s),129.18(s),128.76(s),128.65(s),128.59(s),128.54(s),128.44(s),128.41(s),128.32(s),128.25(s),128.18(s),127.86(s),127.76(s),126.78(s),126.31(s),126.18(s),125.01(d,J=14.1Hz),124.88(s),124.23(s),123.20(s),122.76(s),65.33(d,J=10.1Hz),63.82(d,J=4.9Hz),55.27(d,J=18.0Hz),55.03(d,J=2.1Hz),48.53(d,J=4.1Hz),47.07(s),34.53(s),34.15(d,J=1.1Hz),32.46(s),32.27(s),31.56(s),20.79(s),16.56(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 59 H60 NOP 2 + 860.4145;found 860.4172.

[0074]

[0075] III-1’.White solid.Yield:0.30g,68%. 31 P NMR(121MHz,CDCl 3 )δ-17.66(s),-20.94(s)ppm. 1 H NMR(300MHz,CDCl 3 )δ7.45-7.32(m,10H),7.25-7.09(m,10H),7.05-6.87(m,9H),6.52-6.46(m,1H),3.92(dd,J=9.7,5.4Hz,1H),3.29-3.13(m,2H),2.88(d,J=6.8Hz,1H),2.79-2.73(m,1H),1.63(s,3H),1.59(s,3H),1.49(s,3H),1.45-1.41(m,1H),1.34(s,9H),1.13(s,3H),0.79(t,J=10.5 Hz,1H)ppm. 13 C NMR(75 MHz,CDCl 3)δ152.88(s),151.53(d,J=15.3 Hz),149.82(s),148.16(s),142.27(s),142.18(s),142.05(s),139.06(dd,J=11.6,9.1 Hz),139.03(d,J=2.5 Hz),136.37(d,J=10.6 Hz),135.81(d,J=10.4 Hz),134.40(s),134.14(s),133.91(s),133.64(s),131.23(s),129.65(s),129.30(s),129.15(s),128.73(s),128.62(s),128.56(s),128.50(s),128.41(s),128.38(s),128.29(s),128.15(s),127.82(s),127.73(s),126.74(s),126.27(s),126.14(s),125.00(d,J=13.9 Hz),124.84(s),124.19(s),123.16(s),122.72(s),65.31(d,J=10.3 Hz),63.81(d,J=4.9 Hz),55.27(d,J=18.3 Hz),55.01(d,J=2.3 Hz),48.52(d,J=3.8 Hz),47.02(s),34.50(s),34.14(s),32.42(s),32.23(s),31.53(s),20.76(s),16.52(s)ppm.

[0076]

[0077] White solid.Yield:0.28 g,66%. 31 P NMR(121 MHz,CDCl 3 )δ-17.00(s),-20.62(s)ppm. 1 H NMR(300 MHz,CDCl 3)δ7.58-7.52(m,5H),7.51-7.47(m,16H),7.15–6.99(m,8H),6.67-6.61(m,1H),4.05(dd,J=9.5,5.3 Hz,1H),3.33(dd,J=27.4,13.2 Hz,2H),3.06-2.94(m,2H),2.65(s,1H),2.49(s,3H),1.75(s,3H),1.69(s,3H),1.64(s,3H),1.57-1.49(m,1H),1.27(s,3H),0.96(t,J=10.4 Hz,1H)ppm. 13 C NMR(75 MHz,CDCl 3 )δ152.98(s),151.67(d,J=15.7 Hz),148.42(s),142.43(s),142.26(s),142.21(s),139.35(s),139.07(s),136.69(s),136.54(d,J=10.8 Hz),135.89(d,J=10.0 Hz),134.57(s),134.30(s),133.94(s),133.68(s),131.42(s),129.79(s),129.47(s),129.32(s),128.97(s),128.90(s),128.81(s),128.72(s),128.68(s),128.58(s),128.54(s),128.44(s),128.29(s),128.13(s),127.94(s),126.92(s),126.51(s),126.30(s),125.00(d,J=13.7 Hz),124.43(s),123.37(s),122.91(s),65.81(d,J=9.8 Hz),63.99(d,J=5.0 Hz),55.53(s),55.29(s),53.65(s),48.68(s),47.43(s),34.25(s),32.54(s),32.32(s),21.44(s),20.88(s),16.73(s).

[0078]

[0079] White solid.Yield:66%.MP:69.0-69.7℃.[α] D =+109(c=0.1,CH 2 Cl 2,

[0080] 28.0℃). 31 P NMR(121 MHz,CDCl 3 )δ-16.86(s),-20.42(s)ppm. 1 H NMR(300 MHz,CDCl 3 )δ7.42-7.37(m,5H),7.35-7.26(m,6H),7.23-7.11(m,11H),7.03-6.81(m,8H),6.50-6.46(m,1H),3.87(dd,J=10.1,5.8 Hz,1H),3.15(q,J=13.3 Hz,2H),2.87(d,J=6.9 Hz,1H),2.77(t,J=6.2 Hz,1H),2.38(s,3H),1.62(s,3H),1.57(s,3H),1.49(s,3H),1.38-1.34(m,1H),1.13(s,3H),0.85-0.75(m,1H)ppm. 13 C NMR(101 MHz,CDCl 3)δ152.86(s),151.59(d,J=15.5 Hz),148.24(s),142.26(s),142.16(s),142.09(s),139.27(s),139.00(s),136.52(s),136.40(s),135.85(d,J=10.5 Hz),134.37(s),134.17(s),133.82(s),133.62(s),131.25(s),129.71(s),129.35(s),129.16(s),128.77(s),128.69(s),128.65(s),128.61(s),128.57(s),128.54(s),128.48(s),128.41(s),128.35(s),128.28(s),128.12(s),127.87(s),127.76(s),126.70(s),126.30(s),126.10(s),124.93(d,J=14.0Hz),124.16(s),123.15(s),122.69(s),65.68(d,J=10.2 Hz),63.88(d,J=4.9 Hz),55.41(s),55.19(s),48.50(s),47.09(s),34.13(s),32.32(s),32.13(s),21.22(s),20.70(s),16.48(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 54 NOP 2 + 818.3675;found818.3602.

[0081]

[0082] White solid.Yield:71%.MP:88.2-89.3℃.[α] D =-284(c=0.1,CH 2 Cl 2, 23.4℃). 31 P NMR

[0083] (121 MHz,CDCl 3 )δ-16.76(s),-19.52(s)ppm. 1 H NMR(300 MHz,CDCl 3)δ7.49 -7.46(m,3H),7.41-7.35(m,5H),7.28-7.28(m,6H),7.19-7.16(m,5H),7.13-7.06(m,3H),7.06-6.98(m,3H),6.96-6.95(m,3H),6.60-6.56(m,1H),3.93(dd,J=8.8,6.6 Hz,1H),3.28(q,J=13.4 Hz,2H),3.03(d,J=6.7 Hz,1H),2.83(t,J=6.3 Hz,1H),2.40(s,6H),1.68(s,3H),1.65(s,3H),1.56(s,3H),1.50-1.47(m,1H),1.23(s,3H),1.07(t,J=10.5Hz,1H)ppm. 13 C NMR(101 MHz,CDCl 3)δ152.83(s),151.69(d,J=15.7 Hz),148.26(s),142.53(d,J=2.5 Hz),142.46(s),142.38(s),142.29(s),139.25(d,J=20.9 Hz),137.30(s),136.54(d,J=10.9 Hz),136.01(d,J=10.5 Hz),134.45(s),134.25(s),133.92(s),133.72(s),131.33(s),129.82(s),129.41(s),129.18(s),128.80(s),128.77(s),128.66(s),128.58(s),128.51(s),128.46(s),128.39(d,J=1.5 Hz),128.21(s),127.93(s),127.78(s),126.79(s),126.47(d,J=3.1 Hz),126.31(s),126.17(s),125.06(d,J=14.0Hz),124.23(s),123.26(s),122.76(s),77.42(d,J=11.4 Hz),77.16(s),76.84(s),66.33(d,J=11.2 Hz),64.15(d,J=4.9 Hz),55.55(s),55.22(d,J=17.8 Hz),48.64(d,J=4.7Hz),47.27(s),34.21(s),32.36(s),32.26(s),29.80(s),21.59(s),20.85(s),16.58(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 57 H 56 NOP 2 + 832.3832;found832.3759.

[0084]

[0085] White solid.Yield:85%.MP:133.7-135.2℃.[α] D =-114(c=0.1,CH 2 Cl 2, 28.7℃). 31 PNMR(162 MHz,CDCl 3 )δ-14.02(s),-16.42(s)ppm.1 H NMR(400 MHz,CDCl 3 )δ7.46-7.37(m,5H),7.37-7.30(m,10H),7.24-7.22(m,2H),7.11(m,5H),7.02-6.89(m,3H),6.55(m,1H),3.57(s,2H),2.92(d,J=6.4 Hz,1H),2.85-2.77(m,1H),2.37(t,J=5.7 Hz,1H),1.87(t,J=10.4 Hz,1H),1.65(s,3H),1.62(m,1H),1.59(s,3H),1.48(s,3H),1.37(m,2H),1.28(s,3H),1.08-0.81(m,4H),0.60(t,J=7.1 Hz,3H)ppm. 13 C NMR(101 MHz,CDCl 3 )δ152.83(s),151.89(d,J=16.0 Hz),148.14(s),143.13(s),142.54(d,J=16.0 Hz),139.37(s),139.17(s),136.55(d,J=4.6 Hz),136.43(d,J=4.4 Hz),134.26(s),134.14(s),134.06(s),133.94(s),131.32(s),129.95(s),129.55(s),128.91(s),128.80(s),128.65(s),128.60(s),128.58(s),128.53(s),128.49(s),128.27(s),127.69(s),126.67(s),126.19(s),126.05(s),125.06(d,J=14.4 Hz),123.89(s),123.27(s),122.61(s),64.61(d,J=4.7 Hz),60.07(d,J=12.4 Hz),54.20(s),51.89(d,J=16.2 Hz),49.19(d,J=3.6 Hz),46.44(s),34.27(s),34.16(s),32.58(s),31.57(s),28.04(s),22.76(s),20.95(s),16.39(s),13.96(s).HRMS(ESI)(m / z)[M+H] + Calcd forC 53 H 56 NOP 2+ 784.3846;found 784.3759.

[0086]

[0087] White solid.Yield:75%.MP:115.7-117.8℃.[α] D =-105(c=0.1,CH 2 Cl 2, 31.3℃). 31 PNMR(121 MHz,CDCl 3 )δ-17.76(s),-21.28(s)ppm. 1 H NMR(300 MHz,CDCl 3 )δ7.87(d,J=7.2 Hz,1H),7.45(dd,J=18.6,8.1 Hz,10H),7.32-7.20(m,12H),7.11-7.02(m,4H),6.93(dd,J=16.9,7.2 Hz,2H),6.67-6.61(m,1H),4.38(t,J=7.2 Hz,1H),3.42(d,J=13.5 Hz,1H),3.24(d,J=13.5 Hz,1H),3.02(d,J=6.3 Hz,1H),2.93(t,J=6.3 Hz,1H),2.42(s,3H),1.69(s,3H),1.66(s,3H),1.54(s,3H),1.38(d,J=15.3 Hz,2H),1.30(s,3H)ppm. 13 C NMR(75 MHz,CDCl 3)δ152.82(s),151.82(d,J=15.5 Hz),148.35(s),142.30(s),142.26(s),142.08(s),141.39(d,J=1.8 Hz),139.29(s),139.01(s),136.64(d,J=11.0Hz),136.45(s),136.05(d,J=10.4 Hz),134.47(s),134.20(s),133.93(s),133.66(s),131.41(s),130.04(s),129.90(s),129.47(s),129.12(s),128.89(s),128.69(s),128.65(s),128.59(s),128.54(s),128.45(s),128.33(s),128.25(s),127.85(s),127.73(s),126.83(s),126.60(s),126.30(s),126.22(s),124.99(d,J=14.2 Hz),124.24(s),123.37(s),122.88(s),64.57(d,J=4.6 Hz),55.55(s),55.37(s),49.10(d,J=5.2 Hz),47.06(s),34.25(s),32.30(s),32.12(s),20.94(s),20.57(s),20.53(s),16.55(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 54 NOP 2 + 818.3677;found 818.3602.

[0088]

[0089] White solid.Yield:67%.MP:91.3-92.5℃.[α] D =-75(c=0.1,CH 2 Cl 2, 24.4C). 31 P NMR(121 MHz,CDCl 3 )δ-16.78(s),-19.89(s)ppm. 1 H NMR(300 MHz,CDCl 3)δ7.45-7.38(m,3H),7.36-7.29(m,6H),7.26-7.16(m,9H),7.13-7.06(m,3H),7.04-6.87(m,8H),6.52-6.48(m,1H),3.88(dd,J=9.5,6.1 Hz,1H),3.19(q,J=13.4 Hz,2H),2.91(d,J=6.9 Hz,1H),2.76(t,J=6.4 Hz,1H),2.38(s,3H),1.62(s,3H),1.59(s,3H),1.49(s,3H),1.44-1.38(m,1H),1.15(s,3H),0.93-0.86(m,1H)ppm. 13 C NMR(101 MHz,CDCl 3 )δ152.84(s),151.59(d,J=16.0 Hz),148.20(s),142.39(s),142.28(s),142.20(s),142.12(s),139.22(s),139.01(s),137.47(s),136.44(d,J=11.0 Hz),135.88(d,J=10.1 Hz),134.37(s),134.17(s),133.84(s),133.64(s),131.26(s),129.72(s),129.36(s),129.22(s),129.19(s),129.11(s),128.72(s),128.62(s),128.57(s),128.54(s),128.49(s),128.42(s),128.37(s),128.30(s),128.26(s),128.14(s),127.84(s),127.73(s),126.72(s),126.28(s),125.82(d,J=3.2 Hz),124.95(d,J=14.1 Hz),124.19(s),123.17(s),122.69(s),66.07(d,J=10.7 Hz),63.99(d,J=4.9 Hz),55.30(d,J=6.9Hz),55.08(s),48.55(d,J=4.7 Hz),47.14(s),34.13(s),32.27(s),32.19(s),21.63(s),20.73(s),16.48(s).HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 54 NOP2 + 818.3678;found 818.3602.

[0090]

[0091] White solid.Yield:78%.MP:107.6–110.1℃.[α] D =-96(c=0.1,CH 2 Cl 2, 32.0℃). 31 PNMR(121 MHz,CDCl 3 )δ-16.34(s),-16.49(s)ppm. 1 H NMR(300 MHz,CDCl 3 )δ7.45(m,7H),7.37-7.32(m,10H),7.30(m,2H),7.13(m,4H),7.03(m,1H),6.93(s,1H),6.58(m,1H),3.56(d,J=14.3 Hz,1H),3.41(d,J=14.3 Hz,1H),2.96-2.89(m,2H),2.35(t,J=6.8 Hz,1H),1.67(s,3H),1.65(s,3H),1.51(s,3H),1.33(m,1H),1.31(s,3H),1.23(d,J=6.2 Hz,3H),0.94(m,1H)ppm. 13 C NMR(75 MHz,CDCl 3)δ152.54(s),151.79(d,J=15.6 Hz),147.91(s),142.75(s),139.12(d,J=21.0 Hz),136.52(s),136.37(s),136.21(s),134.21(s),134.14(s),133.94(s),133.87(s),131.39(s),129.83(s),129.42(s),128.86(s),128.81(s),128.76(s),128.63(s),128.59(s),128.57(s),128.54(s),128.48(s),128.43(s),128.27(s),127.80(s),127.17(s),126.77(s),126.24(s),126.20(s),124.91(d,J=14.3Hz),123.99(s),123.30(s),122.74(s),64.73(d,J=4.8 Hz),56.83(d,J=13.7 Hz),55.54(s),54.69(d,J=16.4 Hz),49.02(d,J=3.9 Hz),45.87(s),34.21(s),32.54(s),31.86(s),22.71(s),20.89(s),16.39(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 50 H 50 NOP 2 + 742.3358;found 742.3289.

[0092]

[0093] White solid.Yield:72%%.MP:121.3-124.1℃.[α] D =-125(c=0.1,CH 2 Cl 2, 32.2℃). 31 PNMR(121 MHz,CDCl 3 )δ-14.09(s),-16.34(s)ppm. 1 H NMR(400 MHz,CDCl 3)δ7.49-7.44(m,6H),7.43-7.35(m,11H),7.31-7.29(m,3H),7.22-7.12(m,6H),7.07-6.97(m,3H),6.62-6.57(m,1H),3.65-3.53(m,2H),2.99(d,J=6.0 Hz,1H),2.84-2.77(m,1H),2.42-2.38(m,1H),1.90(t,J=10.4 Hz,1H),1.71(s,3H),1.63(s,3H),1.52(s,3H),1.33(s,3H),0.95-0.93(m,2H),0.92-0.90(m,1H),0.63(t,J=7.2 Hz,3H)ppm. 13 C NMR(101MHz,CDCl 3 )δ152.91(s),151.85(d,J=15.8 Hz),148.02(s),143.18(s),142.32(d,J=15.7 Hz),139.24(d,J=20.1 Hz),136.55(s),136.46(s),136.36(s),134.23(s),134.16(s),134.03(s),133.96(s),131.36(s),129.91(s),129.49(s),128.87(s),128.80(s),128.62(s),128.57(s),128.55(s),128.51(s),128.29(s),127.72(s),127.49(s),126.73(s),126.21(s),126.07(s),124.98(d,J=14.2 Hz),123.89(s),123.29(s),122.61(s),64.74(d,J=4.6 Hz),61.85(d,J=12.7 Hz),54.47(s),51.47(d,J=16.6 Hz),49.01(d,J=3.6 Hz),46.25(s),34.26(s),32.83(s),31.43(s),26.85(d,J=8.6 Hz),20.95(s),16.40(s),10.00(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd forC 51 H 52 NOP 2 + 756.3535;found756.3446.

[0094]

[0095] White solid.Yield:50%.MP:96.5-97.1℃.[α] D =-87(c=0.1,CH 2 Cl 2, 29.8℃). 31 P NMR(162 MHz,CDCl 3 )δ-14.04(s),-16.33(s)ppm. 1 H NMR(400 MHz,CDCl 3 )δ7.50(t,J=7.4Hz,3H),7.47-7.45(m,2H),7.43-7.41(m,5H),7.39-7.36(m,5H),7.32-7.29(m,2H),7.23-7.13(m,5H),7.08-7.03(m,2H),6.99(t,J=7.6 Hz,1H),6.63-6.59(m,1H),3.70-3.59(m,2H),2.98(d,J=6.4 Hz,1H),2.89(p,J=5.8 Hz,1H),2.41(t,J=5.7 Hz,1H),1.98-1.90(m,1H),1.72(s,3H),1.71-1.67(m,1H),1.64(s,3H),1.54(s,3H),1.44-1.37(m,2H),1.35(s,3H),1.13(ddd,J=12.9,11.4,5.8 Hz,1H),0.98-0.91(m,1H),0.63(t,J=7.3Hz,3H)ppm. 13 C NMR(101 MHz,CDCl 3)δ152.91(s),151.91(d,J=15.4 Hz),148.19(s),143.18(s),142.49(d,J=15.9 Hz),139.37(s),139.16(s),136.55(d,J=5.6 Hz),136.44(d,J=5.2 Hz),134.32(s),134.12(s),133.92(s),131.34(s),129.97(s),129.58(s),128.90(s),128.83(s),128.69(s),128.63(s),128.61(s),128.56(s),128.53(s),128.31(s),127.73(s),126.69(s),126.15(d,J=16.5 Hz),125.04(d,J=14.6 Hz),123.92(s),123.31(s),122.63(s),64.63(d,J=4.9 Hz),59.54(d,J=12.5 Hz),54.19(d,J=2.6Hz),52.07(d,J=16.2 Hz),49.11(d,J=3.7Hz),46.43(s),36.84(d,J=9.9 Hz),34.29(d,J=1.2 Hz),32.86(s),31.25(s),20.99(s),19.00(s),16.41(s),14.12(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 52 H 54 NOP 2 + 770.3682;found 770.3602.

[0096]

[0097] White solid.Yield:64%.MP:115.3-117.1℃.[α] D =-37(c=0.1,CH 2 Cl 2, 27.7℃). 31 P NMR(162 MHz,CDCl 3 )δ-13.31(s),-16.11(s)ppm. 1 H NMR(400 MHz,CDCl 3)δ7.45-7.44(m,1H),7.39-7.35(m,9H),7.34-7.31(m,5H),7.26-7.24(m,2H),7.14-7.10(m,3H),7.04-6.99(m,6H),6.96-6.92(m,2H),6.80-6.80(m,2H),6.58-6.58(m,1H),3.57(q,J=15.0 Hz,2H),3.18(p,J=6.1 Hz,1H),3.04(d,J=6.5 Hz 1H),2.85-2.73(m,2H),2.26(t,J=6.0Hz,1H),1.91(t,J=10.5 Hz,1H),1.71-1.67(m,1H),1.64(s,3H),1.62(s,3H),1.47(s,3H),1.30(s,3H),0.93(t,J=6.7 Hz,1H)ppm. 13 C NMR(101 MHz,CDCl 3)δ152.87(s),151.70(d,J=15.5 Hz),147.87(s),142.88(s),142.28(d,J=15.8 Hz),139.24(s),139.01(s),136.55(s),136.43(s),136.33(s),134.22(s),134.11(s),134.02(s),133.91(s),131.22(s),129.76(d,J=1.2Hz),129.48(s),129.33(s),129.04(s),128.79(s),128.74(s),128.63(s),128.59(s),128.56(s),128.52(s),128.45(s),128.20(s),127.80(s),127.67(s),127.33(s),126.64(s),126.10(d,J=10.3 Hz),125.54(s),125.01(d,J=14.4 Hz),123.83(s),123.19(s),122.51(s),64.68(d,J=4.6Hz),61.92(d,J=13.7 Hz),54.38(d,J=3.2 Hz),51.10(d,J=16.3 Hz),49.13(d,J=3.7 Hz),45.85 (s), 40.07(d, J = 11.2 Hz), 34.18 (d, J = 1.1 Hz), 32.30 (s), 31.97 (s), 20.94 (s),16.33 (s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 54 NOP 2 + 818.3678;found 818.3602.

[0098]

[0099] White solid.Yield:57%.MP:87.3-89.1℃.[α] D =-103(c=0.1,CH 2 Cl 2, 32.6℃). 31 P NMR(121 MHz,CDCl 3 )δ-14.51(s),-16.55(s). 1 H NMR(300 MHz,CDCl3 )δ7.46-7.40(m,6H),7.37-7.3(m,12H),7.29-7.26(m,2H),7.17-7.11(m,3H),7.05-7.01(m,2H),6.58-6.54(m,1H),5.60-5.46(m,1H),4.79(dd,J=21.6,13.6 Hz,2H),3.60(d,J=14.6 Hz,1H),3.49(d,J=14.8 Hz,1H),3.01-2.87(m,2H),2.40-2.23(m,3H),1.84(t,J=10.5 Hz,1H),1.66(s,3H),1.63(s,3H),1.48(s,3H),1.30(s,3H),0.89(d,J=2.9 Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ152.88(s),151.81(d,J=16.1 Hz),147.93(s),142.93(s),142.22(d,J=15.9 Hz),139.22(d,J=21.0 Hz),136.55(s),136.45(s),136.35(s),135.45(s),134.19(s),134.17(s),133.98(s),131.34(s),129.85(s),129.44(s),128.96(s),128.79(s),128.60(s),128.56(s),128.48(s),128.25(s),127.68(s),127.29(s),126.71(s),126.18(s),126.07(s),124.99(d,J=14.8 Hz),123.88(s),123.25(s),122.61(s),117.07(s),64.81(d,J=4.8 Hz),60.82(d,J=13.6 Hz),54.68(s),51.58(d,J=16.8 Hz),48.99(s),46.06(s),38.48(d,J=10.8 Hz),34.24(s),32.54(s),31.75(s),20.92(s),16.38(s).HRMS(ESI)(m / z)[M+H] + Calcd for C 52 H 52 NOP 2 + 768.3512;found 768.3446.

[0100]

[0101] White solid.Yield:60%.MP:102.3-103.4℃.[α] D =-6(c=0.1,CH 2 Cl 2, 29.1℃). 31 P NMR(121 MHz,CDCl 3 )δ-5.92(s),-19.68(s)ppm. 1 H NMR(300 MHz,CDCl 3 )δ7.50(dd,J=9.0,1.5 Hz,1H),7.39-7.35(m,15H),7.32-7.18(m,8H),7.11-7.00(m,5H),6.95(d,J=8.3 Hz,1H),3.92-3.83(m,1H),3.65(d,J=13.5 Hz,1H),3.49(d,J=13.5 Hz,1H),2.75(d,J=6.8 Hz,1H),2.59(t,J=6.6 Hz,1H),1.53(s,3H),1.51(s,3H),1.47(s,3H),1.35(s,9H),1.29-1.27(m,1H),1.15(s,3H),1.02-0.94(m,1H)ppm. 13 C NMR(101 MHz,CDCl 3)δ152.92(s),151.30(s),150.02(s),148.93(s),142.12(s),141.78(d,J=15.9 Hz),138.96(s),138.75(s),137.84(d,J=10.8 Hz),133.58(s),133.39(s),132.86(dd,J=21.6,6.8Hz),130.38(s),130.29(s),130.21(s),129.56(s),128.81(s),128.60(s),128.57(s),128.53(s),128.50(s),128.46(s),128.23(s),127.84(s),127.70(d,J=3.3 Hz),127.27(s),126.33(d,J=12.3 Hz),125.66(s),125.05(s),116.78(d,J=6.2 Hz),116.10(s),64.66(d,J=12.1 Hz),64.21(d,J=5.0 Hz),55.51(d,J=2.5Hz),55.09(d,J=17.4 Hz),50.94(s),48.57(d,J=4.2 Hz),34.51(s),34.06(s),32.45(s),32.39(s),31.46(s),20.76(s),16.38(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 59 H 60 NOP 2 + 860.4150;found860.4072.

[0102]

[0103] White solid.Yield:71%.MP:132.3-134.1℃.[α] D =-95(c=0.1,CH 2 Cl 2, 28.4℃). 31 P NMR(121 MHz,CDCl 3 )δ-16.84(s),-20.28(s)ppm. 1 H NMR(300 MHz,CDCl 3)δ7.46-7.41(m,5H),7.38-7.29(m,4H),7.28-7.13(m,12H),7.05-6.91(m,8H),6.53-6.48(m,1H),3.93(dd,J=10.1,5.6 Hz,1H),3.22(s,2H),2.89(d,J=7.0 Hz,1H),2.78(t,J=6.1 Hz,1H),2.53(t,J=9.2 Hz,1H),1.96-1.84(m,4H),1.81-1.78(m,1H),1.65(s,3H),1.60(s,3H),1.52(s,3H),1.48(s,3H),1.15(s,3H),1.04–0.98(m,1H),0.95-0.88(m,2H),0.83-0.76(m,1H). 13 CNMR(101 MHz,CDCl 3 )δ152.86(s),151.56(d,J=15.8 Hz),148.16(s),146.84(s),142.27(s),142.20(s),142.11(s),139.44(d,J=2.1 Hz),139.22(s),139.02(s),136.40(d,J=10.9 Hz),135.87(d,J=10.2 Hz),134.37(s),134.17(s),133.91(s),133.71(s),131.22(s),129.69(s),129.32(s),129.16(s),128.69(s),128.62(s),128.55(s),128.47(s),128.40(s),128.36(s),128.29(s),128.15(s),127.75(s),126.71(s),126.43(s),126.29(s),126.14(s),125.05(d,J=14.5 Hz),124.15(s),123.15(s),122.71(s),65.44(d,J=10.1 Hz),63.84(d,J=4.9 Hz),55.32(d,J=18.5 Hz),55.14(s),48.51(d,J=4.6 Hz),46.91(s),44.30(s),34.60(d,J=6.6 Hz),34.14(s),32.38(s),32.20(s),27.03(s),26.30(s),20.74(s),16.50(s).HRMS(ESI)(m / z)[M+H] +Calcd forC 61 H 62 NOP 2 + 886.4306;found 886.4228.

[0104]

[0105] White solid.Yield:69%.MP:103.8-104.9℃.[α] D =-122(c=0.1,CH 2 Cl 2, 26.6℃). 31 PNMR(162 MHz,CDCl 3 )δ-16.81(s),-20.52(s)ppm. 1 H NMR(400 MHz,CDCl 3 )δ7.42-7.36(m,5H),7.32-7.22(m,5H),7.22-7.07(m,9H),7.00-6.80(m,10H),6.47-6.44(m,1H),3.81(s,1H),3.14(dd,J=33.5,13.4 Hz,2H),2.81(d,J=6.9 Hz,1H),2.73(t,J=6.2 Hz,1H),1.60(s,3H),1.54(s,3H),1.47(s,3H),1.43(s,1H),1.38-1.33(m,1H),1.10(s,3H),0.81-0.74(m,1H)ppm. 13 C NMR(101 MHz,CDCl 3)δ158.68(s),152.87(s),151.54(d,J=16.3Hz),148.25(s),142.19(s),142.11(s),142.02(s),139.07(d,J=21.0 Hz),136.42(d,J=11.1 Hz),135.79(d,J=10.1 Hz),134.37(s),134.17(s),133.78(s),133.59(s),131.25(s),129.66(s),129.34(s),129.15(s),128.71(s),128.67(s),128.58(s),128.54(s),128.48(s),128.42(s),128.35(s),128.27(s),128.22(s),128.13(s),127.90(s),127.77(s),126.73(s),126.33(s),126.12(s),124.87(d,J=13.8 Hz),124.22(s),123.16(s),122.70(s),113.40(s),65.19(d,J=9.9 Hz),63.88(s),55.41(s),55.22(s),48.49(s),47.14(s),34.12(s),32.40(s),32.10(s),26.94(s),20.69(s),16.50(s).HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 53 NO 2 P 2 + 834.3641;found834.3552.

[0106]

[0107] White solid.Yield:74%.MP:115.4-117.1℃.[α] D =-107(c=0.1,CH 2 Cl 2, 28.3℃). 31 PNMR(162 MHz,CDCl 3 )δ-16.64(s),-19.49(s)ppm. 1 H NMR(400 MHz,CDCl 3)δ7.53(s,1H),7.49-7.43(m,3H),7.41-7.35(m,6H),7.31-7.27(m,4H),7.27-7.23(m,4H),7.15-6.88(m,11H),6.57-6.55(m,1H),3.96(dd,J=8.1,6.6 Hz,1H),3.30(d,J=13.5 Hz,1H),3.19(d,J=13.5 Hz,1H),2.93(d,J=6.8 Hz,1H),2.77(t,J=6.3 Hz,1H),2.46(s,1H),1.68(s,3H),1.64(s,3H),1.54(s,3H),1.50-1.48(m,1H),1.23(s,3H),1.08(t,J=10.7 Hz,1H)ppm. 13 C NMR(101 MHz,CDCl 3 )δ152.97(s),151.55(d,J=15.5 Hz),148.22(s),145.09(d,J=3.1 Hz),141.95(s),141.90(s),139.02(s),138.81(s),136.36(d,J=10.4 Hz),135.82(d,J=10.2 Hz),134.40(s),134.20(s),134.04(s),133.83(s),133.63(s),131.34(s),129.72(s),129.49(s),129.33(s),129.03(s),128.84(s),128.70(s),128.66(s),128.59(s),128.53(s),128.48(s),128.41(s),128.25(s),127.91(s),127.86(s),127.82(s),127.26(s),126.84(s),126.76(d,J=3.7Hz),126.42(s),126.29(s),124.85(d,J=13.7Hz),124.45(s),123.32(s),122.80(s),65.77(d,J=11.6 Hz),64.19(d,J=4.9 Hz),55.27(s),55.08(d,J=17.5 Hz),48.69(d,J=5.5 Hz),47.24(s),34.18(s),32.37(s),32.24(s),20.78(s),16.57(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcdfor C55 H 51 ClNOP 2 + 838.3141;found 838.3056.

[0108]

[0109] White solid.Yield:55%.MP:95.8-96.4℃.[α] D =-46(c=0.1,CH 2 Cl 2, 25.7℃). 31 P NMR(121 MHz,CDCl 3 )δ-13.43(s),-15.15(s). 1 H NMR(300 MHz,CDCl 3 )δ7.21-7.44(m,5H),7.39-7.37(m,10H),7.32-7.27(m,2H),7.19-7.12(m,6H),6.58-6.56(m,1H),3.56(dd,J=38.6,14.5 Hz,2H),3.02(d,J=6.2 Hz,1H),2.89-2.80(m,1H),2.44(t,J=6.1 Hz,1H),1.94(t,J=10.4 Hz,1H),1.74(s,3H),1.68(s,3H),1.62-1.55(m,1H),1.51(s,3H),1.34(s,9H),1.34-1.33(m,3H),1.33-1.32(m,2H),1.20(s,9H),0.67(t,J=7.2 Hz,3H). 13 CNMR(75 MHz,CDCl 3)δ152.90(s),149.84(d,J=15.7 Hz),145.91(s),145.24(s),144.85(s),143.14(s),142.31(d,J=16.3 Hz),139.43(s),139.15(s),136.88(d,J=4.6 Hz),136.73(d,J=4.6 Hz),134.25(s),134.19(s),133.98(s),133.92(s),128.92(s),128.9 0(s),128.80(s),128.69(s),128.63(s),128.53(s),128.49(s),128. 45(s),128.39(s),128.36(s),128.29(s),127.88(s),127.76(s),126 .20(s),126.07(s),124.44(s),123.84(d,J=14.0Hz),123.31(s),120. 44(s),64.84(d,J=4.9Hz),62.23(d,J=12.9Hz),54.34(d,J=2.8Hz),51.13(d,J=16.5Hz),49.05(d,J=2.4Hz),46.47(s),34.67(d,J=1.4Hz) ,34.58(s),34.51(s),32.88(s),31.88(s),31.66(s),31.40(s),26.79(d,J=11.2Hz),20.95(s),16.40(s),10.03(s).HRMS(ESI)(m / z)[M+H] + Calcd for C 59 H 68 NOP 2 + 868.4781; found 868.4698.

[0110] 2. Application: Synthesis of spirobarbituric acid-epoxyhexane compounds

[0111] Example P1

[0112] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 30.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester 0.2mmol, 5-benzylidene-1,3-dimethylbarbituric acid 0.1mmol at 5°C. After the reaction, the solvent was removed by extraction, drying, and rotary evaporation, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P1 was 85%.

[0113] Yellow oil.Yield:85%yield.[α] D = +191 (c = 0.055, CH 2 Cl 2 ,33.5℃). 1 H NMR (600

[0114] MHz,CDCl 3 )δ7.35(t,J=7.5Hz,2H),7.31–7.27(m,2H),7.27–7.24(m,2H, overlapped with the peak of chloroform),7.22(d,J=7.5Hz,2H),7.07(d,J=7.1Hz,2H),6.49(s,1H),5.19(d,J=13.6Hz,1H),4.89(s ,1H),4.48(d,J=13.5Hz,1H),3.59(d,J=14.8Hz,1H),3.10(s,3H),2.96(s,3H),2.84(d,J=14.9Hz,1H). 13 C NMR (151 MHz, CDCl 3 )δ169.4,167.3,150.2,136.4,135.8,131.0,129.4,129.0,128.3,128.2,127.0 126.8,125.6,85.1,68.5,58.1,38.2,28.5,27.9.HRMS(ESI)(m / z)[M+H] + Calcd for C 23 H 23 N 2 O 4 +391.1652; found 391.1650.HPLC:The product was analyzed by HPLC to determine the enantiomeric excess:94%ee(Chiralpak AD-H,n-hexane / i-propanol=70 / 30,1mL / min,254nm)t R =6.576min,8.126min, the structural formula of compound P1 is

[0115] In the synthesis of spirobarbituric acid-epoxyhexane compound P1, the ligand used has an important influence on it; the ligand shown in Table 1 is used to replace the 1-phosphanorbornene-dimethyloxanthene ligand III-8 used in this example to synthesize compound P1, and the other methods and parameters are the same. The yield and enantiomeric excess of synthesized P1 are shown in Table 1.

[0116] Table 1 Effect of ligand on the yield and enantiomeric excess of compound P1

[0117]

[0118]

[0119] Among them, the commercially available compounds represented by 1-3 in Table 1 are (S)-(-)-(6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine); (S)-(-)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxadiazole; (S,R,R)-(+)-(3,5-dioxa-4-phosphacycloheptadien[2,1-a:3,4-a′]dinaphth-4-yl)di(1-phenylethyl)amine.

[0120] Under the same conditions of starting reactants, catalyst, solvent and reaction temperature, the spirobarbituric acid-epoxyhexane compound P1 cannot be synthesized using the commercially available compound 1-3 as a ligand; among the 1-phosphanorbornene-dimethyloxanthene ligand compounds III-1 to III-8 synthesized in Examples 1-8, the yield and enantiomeric excess of the synthesized spirobarbituric acid-epoxyhexane compound P1 are the highest when the 1-phosphanorbornene-dimethyloxanthene ligand compound III-8 is used as a ligand.

[0121] Example P2

[0122] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 30.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester 0.2mmol, 1,3-dibenzyl-5-benzylidenebarbituric acid 0.1mmol at 5°C. After the reaction, the solvent was removed by extraction, drying, and rotary evaporation, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P2 was 59%.

[0123] Yellow oil.Yield:59%yield.[α] D = +121 (c = 0.120, CH 2 Cl 2 ,34.3℃). 1 H NMR (600

[0124] MHz,CDCl 3 )δ7.37–7.34(m,4H),7.33–7.31(m,3H),7.30–7.28(m,2H),7.28–7.24(m,4H, overlapped with the peak of chloroform),7.22(d,J=7.5Hz,2H),7.11–7.07(m,1H),6.82(d,J=4.5Hz,4H),6.43(s,1H),5.18(d,J=13.5Hz,1H),4.91(d,J= 15.1Hz,2H),4.83–4.75(m,2H),4.65(d,J=13.9Hz,1H),4.46(d,J=13.5Hz,1H),3.49(d,J=14.6Hz,1H),2.84(d,J=14.7Hz,1H). 13 C NMR (151 MHz, CDCl 3 )δ169.5,166.9,150.3,136.3,136.0,135.7,135.4,130.7,129.6,129.5,129.1,128.7,128.5,128.4,12 8.3,128.2,128.0,127.8,127.2,127.1,126.0,84.4,68.4,57.6,45.5,45.0,39.6.HRMS(ESI)(m / z)[M+H] + Calcd for C 35 H 31 N 2 O 4 +543.2278; found 543.2270.HPLC: The product was analyzed by HPLC to determine the enantiomeric excess: 88%ee (Chiralpak AD-H, n-hexane / i-propanol=95 / 5, 1mL / min, 254nm)t R =14.148min,15.610min, the structural formula of compound P2 is

[0125] Example P3

[0126] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 3 0.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-(4-chlorophenyl)allyl carbonate tert-butyl ester 0.2mmol, 1,3-dibenzyl-5-benzylidenebarbituric acid 0.1mmol at 5°C. After the reaction, the solvent was removed by extraction, drying, and rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P3 was 64%.

[0127] White solid.Yield:64%yield.MP:155.4–155.8℃.[α] D = +113 (c = 0.108, CH 2 Cl 2 ,28.3℃). 1 H NMR (600 MHz, CDCl 3 )δ7.36(t,J=7.6Hz,2H),7.30–7.25(m,4H,overlapped with the peak of chloroform),7.22(d,J=7.6Hz,2H),7.07(d,J=7.0Hz,2H),6.49(s,1H),5.19(d,J=13.5Hz,1H),4.90(s ,1H),4.48(d,J=13.5Hz,1H),3.59(d,J=14.9Hz,1H),3.10(s,3H),2.96(s,3H),2.84(d,J=14.9Hz,1H). 13 C NMR (151 MHz, CDCl 3)δ169.4,167.4,150.2,136.4,135.7,131.0,129.4,129.0,128.3,128.2,12 7.0,126.8,125.6,85.1,68.5,58.1,38.2,28.5,28.0.HRMS(ESI)(m / z)[M+H] + Calcd for C 23 H 21 C1N 2 NaO 4 + 447.1082; found 447.1076.HPLC:The product was analyzed by HPLC to determine the enantiomeric excess:92%ee(Chiralpak AD-H,n-hexane / i-propanol=70 / 30,1mL / min,254nm)t R =6.520min,7.995min, the structural formula of compound P3 is

[0128] Example P4

[0129] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 3 0.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-(4-methylphenyl)allyl carbonate tert-butyl ester 0.2mmol, 1,3-dibenzyl-5-benzylidenebarbituric acid 0.1mmol at 5°C. After the reaction, the solvent was removed by extraction, drying, and rotary evaporation, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P4 was 59%.

[0130] White oil.Yield:59%yield.[α] D = +70 (c = 0.160, CH 2 Cl 2 ,29.5℃). 1 H NMR (600 MHz, CDCl 3)δ7.30–7.24(m,3H, overlapped with the peak of chloroform),7.16(d,J=7.8Hz,2H),7.11(d,J=7.8Hz,2H),7.06(d,J=7.2Hz,2H),6.45(s,1H),5.19(d,J=13.5Hz,1H),4. 89(s,1H),4.48(d,J=13.5Hz,1H),3.57(d,J=14.9Hz,1H),3.10(s,3H),2.96(s,3H),2.83(d,J=14.9Hz,1H),2.35(s,3H). 13 C NMR (151 MHz, CDCl 3 )δ169.5,167.4,150.2,136.7,135.8,133.5,130.2,129.4,129.0,129.0,128.2 ,126.8,125.6,85.1,68.6,58.2,38.2,28.5,27.9,21.2.HRMS(ESI)(m / z)[M+H] + Calcd for C 24 H 24 N 2 NaO 4 + 427.1628; found 427.1624.HPLC:The product was analyzed by HPLC to determine theenantiomeric excess:92%ee(Chiralpak AD-H,n-hexane / i-propanol=70 / 30,1mL / min,254nm)t R =7.877min, 10.468min, the structural formula of compound P4 is

[0131] Embodiment P5

[0132] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 30.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-(4-fluorophenyl)allyl carbonate tert-butyl ester 0.2mmol, 1,3-dibenzyl-5-benzylidenebarbituric acid 0.1mmol at 5°C. After the reaction, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P5 was 52%.

[0133] Yellow oil.Yield:52%yield.[α] D = +73 (c = 0.080, CH 2 Cl 2 ,33.5℃). 1 H NMR (600 MHz, CDCl 3 )δ7.30–7.25(m,3H, overlapped with the peak of chloroform),7.21–7.17(m,2H),7.09–7.02(m,4H),6.44(s,1H),5.13(d,J=13.5Hz,1H),4.89(s,1H ),4.46(d,J=13.5Hz,1H),3.58(d,J=14.9Hz,1H),3.10(s,3H),2.97(s,3H),2.82(d,J=14.9Hz,1H). 13 C NMR (151 MHz, CDCl 3 )δ169.3,167.4,161.8(d,J=246.6Hz),150.1,135.6,132.4(d,J=3.3Hz),131.1,130.7,130.6,12 9.5,128.2,125.7,125.6,115.3,115.2,85.1,68.3,58.1,38.1,28.5,27.9.HRMS(ESI)(m / z)[M+H] + Calcd for C 23 H 22 FN 2 O 4 +409.1558; found409.1557.HPLC:The product was analyzed by HPLC to determine the enantiomericexcess:89%ee(Chiralpak AD-H,n-hexane / i-propanol=70 / 30,1mL / min,254nm)t R =7.434min,9.561min, the structural formula of compound P5 is

[0134] Example P6

[0135] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 3 0.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-(1-naphthyl)allyl carbonate tert-butyl ester 0.2mmol, 1,3-dibenzyl-5-benzylidenebarbituric acid 0.1mmol at 5°C. After the reaction, the solvent was removed by extraction, drying, and rotary evaporation, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P6 was 76%.

[0136] Yellow oil.Yield:76%yield.[α] D =-56(c=0.080,CH 2 Cl 2 ,27.5℃). 1 H NMR (600

[0137] MHz,CDCl 3 )δ7.84–7.80(m,3H),7.65(s,1H),7.49–7.44(m,2H),7.40–7.37(m,1H),7.32–7.24(m,3H, overlapped with the peak of chloroform),7.10–7.05(m,2H),6.63(s,1H),5.28(d,J=13.5Hz,1H),4.92(s,1H),4.56(d ,J=13.6Hz,1H),3.64(d,J=14.9Hz,1H),3.12(s,3H),2.98(s,3H),2.90(d,J=14.9Hz,1H). 13 C NMR (151 MHz, CDCl3 )δ169.4,167.4,150.2,135.8,133.9,133.3,132.4,131.5,129.4,128.2,128.0,127.9,127.8,12 7.7,127.3,126.8,126.2,125.9,125.6,85.1,68.6,58.2,38.3,28.5,28.0.HRMS(ESI)(m / z)[M+H] + Calcd for C 27 H 25 N 2 O 4 + 441.1809; found 441.1831.HPLC: The product was analyzed by HPLC to determine the enantiomeric excess:92%ee(ChiralpakAD-H,n-hexane / i-propanol=85 / 15,1mL / min,254nm)t R =9.020min,11.719min, the structural formula of compound P6 is

[0138] Example P7

[0139] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 3 0.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester 0.2mmol, 5-(4-phenylbenzylidene)-1,3-dimethylbarbituric acid 0.1mmol at 5°C. After the reaction, the solvent was removed by extraction, drying, and rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P7 was 96%.

[0140] White solid.Yield:96%yield.MP:64.8–65.2℃.[α] D = +39 (c = 0.200, CH 2 Cl 2 ,

[0141] 34.2℃). 1 H NMR (600 MHz, CDCl 3)δ7.52(d,J=7.6Hz,2H),7.49(d,J=7.6Hz,2H),7.42(t,J=7.3Hz,2H),7.36(t,J=7.8Hz,3H),7.28–7.21(m,3H, overlapped with the peak of chloroform),7.14(d,J=7.7Hz,2H),6.49(s,1H),5.21(d,J=13.5Hz,1H),4.95(s,1H),4.49 (d,J=13.5Hz,1H),3.59(d,J=14.8Hz,1H),3.14(s,3H),2.99(s,3H),2.86(d,J=14.8Hz,1H). 13 C NMR (151 MHz, CDCl 3 )δ169.5,167.4,150.1,142.3,140.2,136.4,134.8,131.0,129.1,128.8,128.3,127.7,12 7.2,127.0,126.9,126.9,126.1,84.8,68.5,58.1,38.3,28.6,28.0.HRMS(ESI)(m / z)[M+H] + Calcd for C 29 H 27 N 2 O 4 + 467.1965; found467.1961.HPLC: The product was analyzed by HPLC to determine the enantiomericexcess:91%ee(Chiralpak AD-H,n-hexane / i-propanol=85 / 15,1mL / min,254nm)t R =11.372min,15.922min, the structural formula of compound P7 is

[0142] Example P8

[0143] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 30.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester 0.2mmol, 5-(4-fluorobenzylidene)-1,3-dimethylbarbituric acid 0.1mmol at 5°C. After the reaction, the solvent was removed by extraction, drying, and rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P8 was 74%.

[0144] White solid.Yield:74%yield.MP:146.6–147.2℃.[α] D = +156 (c = 0.059, CH 2 Cl 2 ,

[0145] 25.3℃). 1 H NMR (600 MHz, CDCl 3 )δ7.36(t,J=7.6Hz,2H),7.27(t,J=9.1Hz,2H),7.22(d,J=7.5Hz,2H),7.09–7.05(m,1H, overlapped with the peak of chloroform),6.96(t,J=8.6Hz,2H),6.48(s,1H),5.18(d,J=13.5Hz,1H),4.90(s,1H),4.47 (d,J=13.5Hz,1H),3.57(d,J=14.8Hz,1H),3.13(s,3H),3.00(s,3H),2.83(d,J=14.9Hz,1H). 13 CNMR (151MHz, CDCl 3 )δ169.4,167.2,163.0(d,J C-F =248.8Hz),150.1,136.3,131.8(d,J C-F =3.3Hz),130.7,127.5,127.5,127.1(d,J C-F =8.2Hz),115.3(d,J C-F =21.6Hz),84.2,68.5,58.0,38.4,28.6,28.0.HRMS(ESI)(m / z)[M+H] + Calcd for C 23 H 22 FN 2 O 4+ 409.1558; found409.1556.HPLC: The product was analyzed by HPLC to determine the enantiomericexcess:94%ee(Chiralpak AD-H, n-hexane / i-propanol=85 / 15, 1mL / min, 254nm)t R =10.595min,11.809min, the structural formula of compound P8 is

[0146] Embodiment P9

[0147] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 3 0.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester 0.2mmol, 5-(2,4-difluorobenzylidene)-1,3-dimethylbarbituric acid 0.1mmol at 5°C. After the reaction, the solvent was removed by extraction, drying, and rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P9 was 71%.

[0148] White solid.Yield:71%yield.MP:188.8–189.2℃.[α] D = +118 (c = 0.055, CH 2 Cl 2 ,

[0149] 31.8℃). 1 H NMR (600 MHz, CDCl 3 )δ7.36(t,J=7.6Hz,2H),7.28–7.24(m,3H,overlapped with the peak of chloroform),7.21(d,J=7.5Hz,2H),6.86–6.82(m,1H),6.77–6.72(m,1H),6.52(s,1H),5.17–5.13(m, 2H), 4.49 (d, J = 13.6Hz, 1H), 3.58 (d, J = 14.9Hz, 1H), 3.19 (s, 2H), 2.98 (s, 2H), 2.93 (d, J = 15.0Hz, 1H). 13C NMR (151 MHz, CDCl 3 )δ168.3,167.5,163.2(dd,J C-F =255.2Hz),158.9(dd,J C-F =250.7Hz),150.3,136.3,130.7,129.2(q,J C-F =9.3Hz),129.0,128.3,127.1(d,J C-F =11.5Hz),119.5(dd,J C-F =13.6Hz),111.7(dd,J C-F =18.2Hz),103.4,103.39(d,J C-F =26.7Hz),68.8,57.8,37.5,29.7,28.8,28.1.HRMS(ESI)(m / z)[M+H] + Calcd for C 23 H 20 F 2 N 2 NaO 4 + 449.1283; found 449.1276.HPLC:The product was analyzed by HPLC to determine the enantiomeric excess:94%ee(Chiralpak AD-H,n-hexane / i-propanol=98 / 2,1mL / min,254nm)t R =33.712min, 36.197min, the structural formula of compound P9 is

[0150] Example P10

[0151] In a 10 mL reaction bottle, Pd was added under nitrogen atmosphere. 2 (dba) 3 0.005mmol, 1-phosphanorbornene-dimethylxanthene ligand 0.008mmol, DBN 0.08mmol, in 2mL ethyl acetate solution, stirred at room temperature for 0.5 hours, then added 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester 0.2mmol, 5-(4-trifluoromethylbenzylidene)-1,3-dimethylbarbituric acid 0.1mmol at 5°C. After the reaction, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product compound P10 was 66%.

[0152] White solid. Yield: 66% yield. MP: 100.5–100.9 °C. [α] D = +197 (c = 0.070, CH 2 Cl 2 ,

[0153] 25.3 °C). Figure 2 as shown 1 H NMR (600 MHz, CDCl 3 ) δ 7.53 (d, J = 8.0 Hz, 2H), 7.38–7.34 (m, 2H), 7.29–7.25 (m, 1H, overlapped with the peak of chloroform), 7.25–7.20 (m, 4H), 6.49 (s, 1H), 5.19 (d, J = 13.5 Hz, 1H), 5.01 (s, 1H), 4.48 (d, J = 13.5 Hz, 1H), 3.56 (d, J = 14.7 Hz, 1H), 3.15 (s, 3H), 2.97 (s, 3H), 2.86 (d, J = 14.8 Hz, 1H). 13 C NMR (151 MHz, CDCl 3 ) δ 169.3, 166.9, 150.0, 140.1, 136.2, 131.5 (q, J C-F = 32.9 Hz), 130.3, 129.0, 128.4, 127.4, 127.2, 125.2 (d, J C-F = 3.4 Hz), 123.7 (q, J C-F = 272.5 Hz), 83.8, 68.4, 57.7, 38.8, 28.6, 28.0. HRMS (ESI) (m / z) [M + H] + Calcd for C 24 H 22 F 3 N 2 O 4 + 459.1526; found 459.1527. HPLC: The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (Chiralpak IA-H, n-hexane / i-propanol = 95 / 5, 1 mL / min, 254 nm) t R = 17.308 min, 20.796 min, The structural formula of compound P10 is

[0154] The compound P10 was subjected to cytotoxicity analysis using the classic MTT method. The specific test method is as follows: HeLa tumor cells were inoculated in a 96-well plate, and three replicate wells were set for each concentration. After the cells adhered to the wall and grew, the cells were treated with drugs at different concentrations for 24 hours. After the drug effect ended, MTT solution was added (MTT mother solution was 5 mg / mL, 10 μL per well), and the plate was placed in an incubator and continued to be cultured for ~4 hours. After the culture was terminated, the culture medium was carefully aspirated, and DMSO (100 μL per well) was added using a spray gun, and the plate was shaken on a shaker in the dark for 10 minutes to ensure that the purple formazan crystals formed could be completely dissolved. Place the plate in an enzyme reader and read the optical density OD value at 490 nm. The cell viability was calculated according to the formula and the fluorescence intensity of the blank control group, and then the IC of compound P10 was calculated. 50 The value is 6.86 μmol / L. Figure 3 shown.

[0155] Therefore, the present invention optimizes the catalyst, solvent, catalyst equivalent and reaction temperature and other conditions, and finds that when III-8 is used as a ligand, the synthesis of spirobarbituric acid-epoxyhexane compounds is the best. By changing the substituents at various positions on the reaction substrate, the substrate applicability of such reactions is further studied, so that the yield of spirobarbituric acid-epoxyhexane compounds can reach 96%, the diastereoselectivity is greater than 20:1, and the stereoselectivity is greater than 98%.

[0156] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solution of the present invention, which should be included in the scope of the technical solution for protection of the present invention.

Claims

1. A 1-phosphanorbornene-dimethylxanthene chiral ligand, characterized in that: The structural formula is shown in the following formula III or III': Wherein, in the structural formula, the group R is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkenyl, phenyl, halogenated phenyl, C 1-6 Alkyl substituted phenyl or C 1-6 Alkoxy substituted phenyl group, group R 1 C 1-6 alkyl.

2. The chiral ligand according to claim 1, characterized in that The group R is methyl, ethyl, propyl, butyl, allyl, phenyl, benzyl, 4-tert-butylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyclohexylphenyl, 2-methylphenyl, 3-methylphenyl, 3-chlorophenyl or 3,5-dimethylphenyl. 1 It is hydrogen or tert-butyl.

3. The chiral ligand according to claim 2, characterized in that It is one of the following structural formulas:

4. A method for synthesizing a chiral ligand according to any one of claims 1 to 3, comprising using a 9,9-dimethyloxanthene compound and a 1-phosphanorbornene amine compound as raw materials, and generating the 1-phosphanorbornene-dimethyloxanthene chiral ligand by H[1,5] migration and phospha-DA reaction, wherein: The structural formula of the 9,9-dimethylxanthene compound is shown in Formula I below, and the structural formula of the 1-phosphanorborneneamine compound is shown in Formula II or II' below; the reaction formula is shown below:

5. The synthesis method according to claim 4, characterized in that The desiccant is anhydrous magnesium sulfate or anhydrous sodium sulfate, the reducing agent is sodium borohydride or sodium cyanoborohydride, and the first organic solvent is anhydrous methanol, ethanol, dichloromethane or tetrahydrofuran.

6. The synthesis method according to claim 4 or 5, characterized in that: The synthesis method specifically includes: placing the 9,9-dimethyloxanthene compound and the 1-phosphanorbornene amine compound in a first Schlenk flask, adding the first organic solvent and the desiccant, and heating and refluxing at 60 to 80° C. until the reaction is complete; placing the reaction system in an ice water bath, adding the reducing agent, and then continuing the reaction in the ice water bath until the reaction is complete, quenching the reaction, and synthesizing the 1-phosphanorbornene-dimethyloxanthene chiral ligand.

7. The synthesis method according to claim 6, characterized in that After the 1-phosphanorbornene-dimethyloxanthene chiral ligand is synthesized, it is extracted with ethyl acetate, the organic layers are combined, dried with MgSO4, filtered, the solvent is evaporated under reduced pressure, and the purified 1-phosphanorbornene-dimethyloxanthene chiral ligand is obtained by column chromatography separation.

8. The synthesis method according to claim 4, 5 or 7, characterized in that: The synthesis method of the compound I comprises the following steps: Synthesis of compound I-2: First, compound I-1 and n-butyl lithium are used as raw materials to undergo lithiation reaction in an ice-water bath, and then iodine is added to react at room temperature to synthesize compound I-2. The reaction formula is as follows: Synthesis of compound I: First, the compound I-2 and n-butyl lithium are reacted at low temperature as raw materials, diphenylphosphine chloride is added to react, and then n-butyl lithium is added to react under alkaline conditions to synthesize the compound I. The reaction formula is as follows:

9. The synthesis method according to claim 4, 5 or 7, characterized in that: The synthesis method of the 1-phosphanorbornene amine compound comprises the following steps: Synthesis of compound II-4: Compound II-3, tert-butylsulfenamide and tetraisopropyl titanate are used as raw materials to undergo a condensation reaction to generate compound II-4. The reaction formula is as follows: Synthesis of compounds II-5 and II-5': Compound II-4 and Grignard reagent RMgBr were used as raw materials, and compounds II-5 and II-5' were synthesized in an ice-water bath. The reaction formula is as follows: Synthesis of compound II: The compound II-5 or II-5' is first subjected to a reduction reaction under nickel catalysis, and then reacted with dilute hydrochloric acid to remove the sulfinyl group, thereby synthesizing the 1-phosphanorborneneamine compound II or II'. The reaction formula is as follows:

10. Use of the chiral ligand according to any one of claims 1 to 3 in the preparation of spirobarbituric acid-epoxyhexane compounds, wherein: The structural formula of the spirobarbituric acid-epoxyhexane compound is The group R in this structural formula 2 C 1-6 Alkyl, C 1-6 Alkoxy, hydrogen, halogen, haloC 1-6 Alkyl, nitro or naphthyl, group R 3 C 1-6 Alkyl, C 1-6 Alkoxy, hydrogen, halo or naphthyl; the group R 4 C 1-6 Alkyl, or benzyl.

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